Cross-species transmission of pathogens is a major threat to public health worldwide and accounts for 75% of emerging human infectious diseases. Bats act as asymptomatic reservoir hosts for numerous zoonotic viruses, that are lethal in humans and for which no vaccines or specific therapeutics exist, indicating that the chiropteran immune system can control these viruses. Although there has been a recent growing interest in the peculiarities of bat innate immunity, their humoral immune response remains unexplored at the molecular level despite its known participation to fighting off pathogens. Previous studies revealed unusually fast bat B cell proliferation, compared to other mammals, and an exceptional immunoglobulin combinatorial diversity, suggesting a possible way these mammals successfully cope with an astounding diversity of viruses. We propose that the long co-evolution of bats with viruses could have led to the presence of highly specific immunoglobulin variable heavy chain segments playing a role in successfully controlling pathogens and that bat antibodies represent an untapped source of viral inhibitors. The proposed project will illuminate the role of bat humoral immunity in controlling pathogen infections, identify novel therapeutics against zoonotic viruses and guide the computational design of next-generation protein inhibitors of viral entry. This work will generate tools to combat emerging and re-emerging zoonotic viruses, including some pathogens that have not yet emerged or been discovered, and will be key to assist pandemic preparedness effort.